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Background: The anatomical approach for the management of para-Hisian ventricular arrhythmias (VAs) with QRS morphological changes after catheter ablation (CA) has not been well investigated., Objective: We aimed to evaluate the electrocardiographic and electrophysiological findings and ablation outcomes of para-Hisian VAs with QRS morphological changes after CA., Methods: Of the 30 patients who underwent CA for para-Hisian VAs at 4 institutions, 10 (33%) had QRS morphological changes after ablation. All 10 patients underwent an anatomical approach, targeting the site anatomically opposite to the site where the QRS morphology had been changed by ablation. We investigated the safety and efficacy of the anatomical approach., Results: Of the 10 patients evaluated, the approach was switched from the right ventricular septum to the left ventricular septum/aortic root in 7 (70%) (RL group) whereas 3 (30%) underwent left-to-right switches (LR group). After CA, the precordial transition zone tended to be earlier in the RL group and later in the LR group. In the RL group, successful VA suppression was achieved, despite suboptimal pace map concordance from the left side or a relatively delayed earliest activation time. Of the 10 patients who underwent an anatomical approach, 8 (80%) had procedural success, and ablation was discontinued in 1 (10%) because of the risk of atrioventricular block., Conclusion: The anatomical approach showed promising results regarding safety and efficacy. Therefore, it should be considered when QRS morphological changes are observed during or after CA of para-Hisian VAs., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Very high power and short duration (vHPSD) ablation is recently used for pulmonary vein isolation. However, low first-pass isolation rates have been reported, possibly because of shallow lesion formation, necessitating deeper lesions to improve treatment outcomes., Objective: This study aimed to confirm the safety and efficacy of double radiofrequency applications of vHPSD ablation in an in vivo beating swine heart model., Methods: Eighteen swine were anesthetized and underwent vHPSD ablation using the QDOT-MICRO catheter at 90 W for 4 seconds, targeting a contact force of 10 g. Radiofrequency applications were performed as single application (SA) and double applications (DA) with 4-8 seconds rest intervals. Lesion surface area and volume were measured postablation., Results: A total of 337 atrial lesions and 74 ventricular lesions were created. Both 4-6 seconds DA and 7-8 seconds DA produced significantly larger and deeper lesions than did SA, with atrial surface lengths averaging 9.0 mm for 4-6 seconds DA, 9.2 mm for 7-8 seconds DA, and 8.0 mm for SA. Transmurality was observed at 100% for 4-6 seconds and 7-8 seconds DAs, while it was 94% for SA (P = .002). Ventricular lesion metrics followed similar trends. Except for 1 event of tiny char formation during 4 seconds DA in the ventricle, neither steam pops nor char formation was observed in either the atrium or the ventricle., Conclusion: In an in vivo swine heart model, DA with 4-6 seconds and 7-8 seconds intervals create deeper and wider lesions than does SA, suggesting its potential for clinical application in areas with thicker myocardial walls. However, DA with very short intervals may still pose a risk of excessive tissue heating., Competing Interests: Disclosures Drs Goto, Takigawa, and Miyazaki received endowments from Medtronic Japan, Boston Scientific, Japan Lifeline, and Win International. No other authors have conflict of interest to declare., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Left atrial epicardial adipose tissue (LA-EAT) is associated with the recurrence of atrial tachyarrhythmias (AF/AT) after catheter ablation for atrial fibrillation (AF). However, no previous studies have assessed the predictive value of segment-specific LA-EAT volumes for AF/AT recurrence. This study aimed to assess the relationship between segmental LA-EAT volume and AF/AT recurrence., Methods: This study included 350 consecutive patients who underwent initial AF ablation (53.7 % paroxysmal AF (PAF)). Preoperative multidetector row computed tomography assessed LA-EAT, categorized into three segments: anterior-EAT, posterior-EAT, and interatrial septal adipose tissue (IAS-AT)., Results: During a mean follow-up period of 351 ± 109 days, 56 patients (16.0 %) experienced AF/AT recurrence. The mean LA-EAT volume was 20.7 ± 11.1 ml and LA-EAT ≥26.8 ml was an independent risk factor for AF/AT recurrence (HR 2.21, 95 % confidence interval (CI): 1.24-3.93, P = 0.007). Receiver operating characteristic analyses revealed the area under the curve for IAS-AT was 0.669 (95 % CI: 0.596-0.743) with an optimal cut-off point of 1.3 ml (sensitivity 76.8 %; specificity 50.0 %), significantly outperforming the anterior- and posterior-EAT in predicting recurrent AF/AT. Multivariate analysis indicated IAS-AT was an independent predictor of AF/AT recurrence in patients with persistent AF (PeAF) (HR 3.52, 95 % CI: 1.52-8.13, P = 0.003), but not in patients with PAF., Conclusions: LA-EAT predicts AF/AT recurrence after AF ablation, with IAS-AT proving significantly more effective than other LA-EAT segments in predicting recurrence. Notably, IAS-AT emerged as an independent predictor of AF/AT recurrence in patients with PeAF but not in those with PAF., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Unipolar electrograms (uni-EGMs) are an essential part of intracardiac mapping. Although Wilson central terminal (WCT) is conventionally used as a reference for signals, avoidance of contamination by far-field and nonphysiologic signals is challenging., Objective: The aim of the study was to explore the impact of an intracardiac indifferent reference electrode close to the recording electrodes, in lieu of WCT, on electrograms., Methods: Sinus node activation was mapped in patients undergoing catheter ablation by a multielectrode array with a close indifferent electrode (CIE) embedded in the distal end of the catheter shaft. An equal number of points was sequentially acquired at each site with use of CIE as a reference first and subsequently with WCT. Uni-EGMs, bipolar EGMs, and the earliest activation area (defined as the area activated in the first 10 ms of the beat) were compared between CIE- and WCT-based activation maps., Results: Seventeen patients (61 ± 18 years; 76% male) were studied. Uni-EGM voltages acquired with CIE were significantly larger than (n = 11) or comparable to (n = 4) those acquired with WCT. When points from the entire cohort were analyzed altogether, unipolar voltages and their maximum negative dV/dT and bipolar voltages recorded with CIE were significantly larger than those recorded with WCT (2.36 [1.42-3.79] mV vs 1.96 [1.25-3.03] mV, P < .0001; 0.40 [0.18-0.77] mV/s vs 0.35 [0.15-0.71] mV/s, P < .0001; and 1.46 [0.66-2.81] mV vs 1.33 [0.54-2.64] mV, P < .0001, respectively). The earliest activation area was significantly smaller in CIE-based activation maps than in WCT-based ones (0.3 [0.7-1.4] cm 2 vs 0.6 [1.0-1.8] cm 2 , P = .01)., Conclusion: CIE-based maps were associated with an approximately 20% increase in unipolar voltage and may highlight the origin of a focal activation more clearly than WCT-based ones., Competing Interests: Disclosures Drs Goto, Takigawa, and Miyazaki belong to the division that receives endowments from Medtronic Japan, Boston Scientific, Japan Lifeline, APEX, and WIN International. No other authors have conflict of interest to declare., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Ethanol infusion into the vein of Marshall (EIVOM) has been performed as an adjunctive atrial fibrillation therapy. However, the time course change, quantitative lesion investigation, and effects on epicardial fat pads and fractionated atrial electrograms created by EIVOM have never been investigated., Objective: This study aimed to perform a quantitative analysis of lesions created by EIVOM., Methods: We created voltage maps using a 3-dimensional mapping system immediately before and 30 minutes and 60 minutes after performing EIVOM to study the time course change in the lesions. We compared differences in the average contact force value required for successful conduction block in the Marshall vein area of patients with and without EIVOM. We also investigated effects of EIVOM on the area of complex fractionated atrial electrograms before and after EIVOM. We measured the total epicardial fat pad volume before and after EIVOM by computed tomography., Results: Voltage was significantly reduced after EIVOM, and there were significant differences in voltage reduction between the control status and 30 minutes and 60 minutes after EIVOM (P < .05). The average contact force value was significantly lower with vs without EIVOM (P < .05). The total epicardial fat volume and complex fractionated atrial electrogram area also significantly decreased after EIVOM (P < .05)., Conclusion: EIVOM provided significant therapeutic effects on the left atrial tissue perpetuating atrial fibrillation, which was demonstrated by a quantitative analysis., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Early recurrence of atrial tachyarrhythmias (ERAT) within 3 months of thermal ablation for atrial fibrillation (AF) is common and often considered transient. Pulsed field ablation (PFA) is a nonthermal energy source in which ERAT is not well described., Objective: The purpose of this study was to analyze ERAT in patients with AF undergoing PFA in the Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF (PULSED AF) trial., Methods: This analysis included 154 (52.4%) paroxysmal AF and 140 (47.6%) persistent AF who had ≥10 rhythm assessments during the 90-day blanking period. ERAT was defined as any instance of ≥30 seconds of AF, atrial flutter, or atrial tachycardia on transtelephonic monitoring (weekly and symptomatic) or ≥10 seconds on electrocardiography (at 3 months), both within 90 days. Late recurrence of atrial tachyarrhythmias (LRAT) was defined as observed atrial tachyarrhythmias between 90 days and 12 months., Results: The overall prevalence of ERAT was 27.1% in patients with paroxysmal AF and 31.6% in patients with persistent AF. In patients with ERAT, 73% had ERAT onset within the first month of the procedure. The presence of ERAT was associated with LRAT in patients with paroxysmal AF (hazard ratio 6.4; 95% confidence interval 3.6-11.3) and patients with persistent AF (hazard ratio 3.8; 95% confidence interval 2.2-6.6). Yet, in 29.4% of patients with paroxysmal AF and 34.3% of patients with persistent AF with ERAT, LRAT was not observed. LRAT was positively correlated with the number of ERAT observations., Conclusion: ERAT after PFA predicted LRAT in patients with paroxysmal and persistent AF. However, the concept of a blanking period after PFA is still valid, as approximately one-third of patients with ERAT did not continue to have LRAT during follow-up and may not need reablation., Competing Interests: Disclosures Dr Tarakji, Mr Cerkvenik, and Dr van Bragt are employees and stockholders of Medtronic. Dr Boersma’s cardiology department receives consultation funds from Medtronic, Boston Scientific (BS), Abbott Medical (AM), Adagio Medical, and ZOLL. Dr Natale receives grants and/or consultation funds from Medtronic, Abbott, Biosense Webster (BW), Biotronik, BS, and iRhythm. Dr Haines receives grants and/or consultation funds from Medtronic. Dr DeLurgio receives grants, consultation funds, and/or honoraria funds from Medtronic, AtriCure, and BS. Dr Sood receives consultation or honoraria funds from Johnson & Johnson, Abbott, BS, AtriCure, Bristol Myers Squibb, and Pfizer. Dr Marchlinski receives grants, consultation funds, and/or honoraria funds from Medtronic, BW, AM, and Biotronik. Dr Calkins receives grants, consultation funds, and/or honoraria funds from Medtronic, BS, AM, AtriCure, and BW. Dr Hoyt receives grants and/or consultation funds from Medtronic and AM. Dr Sanders receives grants, consultation funds, and/or honoraria funds from Medtronic, BS, AM, Becton Dickinson, PaceMate, and CathRx. Dr Packer receives grants and/or consultation funds from Medtronic. Dr Mittal receives consultation funds from Medtronic and BS. Dr Di Biase is a consultant for BW, Stereotaxis, and iRhythm and has received speaker honoraria/travel from BW, AM, BS, Medtronic, Biotronik, AtriCure, Siemens, and ZOLL. Dr Tada receives honoraria and/or grants from Medtronic, Daiichi Sankyo, AM, Nippon Boehringer Ingelheim, Eli Lilly, Otsuka Pharmaceutical, Marubun Tsusyo, Biotronik, Bristol Myers Squibb, BS, and Novartis Pharma. Dr Tomita receives research funding from Boehringer Ingelheim, Bayer, Daiichi Sankyo, BS, AM, and Biotronik and speakers’ honorarium from Boehringer Ingelheim, Bayer, Daiichi Sankyo, and Bristol Myers Squibb. Dr Tomita is also a concurrent professor of an endowment department supported by Medtronic Japan, Japan Lifeline, and Fukuda Denshi Kitatohoku Hanbai. Dr Kuck receives grants and/or consultation funds from Medtronic and Cardiovalve. Dr Verma receives grants and/or consultation funds from Medtronic, BW, Bayer, MedLumics, Adagio Medical, and BS. The others have nothing to declare., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Slow pathway elimination of the atrioventricular node (AVN) is essential to treat AVN reentrant tachycardia (AVNRT). However, injury to the AVN conduction (IAVN) is one of the serious complications. Cryofreezing energy is expected to reduce the incidence of IAVN. This study aimed to investigate the usefulness of a novel method to avoid IAVN during cryoablation of AVNRT., Methods: A total of 157 patients (average age, 65.8 years; male, 71) suffering from AVNRT were included. Once the AVNRT terminated during cryo-ablation, then rapid atrial constant pacing (RACP) was performed during freezing at a rate lower 10 bpm than that inducing Wenchebach AV block in 74 (47.1 %) patients (Group A). The RACP rate was decreasingly reduced by 10 bpm in case of the occurrence of IAVN. When the RACP reached 100 bpm, the cryoablation was prematurely terminated. Group B patients (83 = 52.9 %) underwent cryoablation during sinus rhythm. All patients were allocated in a randomized fashion. We compared the severity of the IAVN between Groups A and B., Results: There were no significant differences at 12 months regarding the freedom from the AVNRT between Groups A and B. However, the duration of the IAVN was significantly longer in Group B than A (p = 0.02). There were no significant differences regarding the distance between the His recording sites and successful ablation sites between Groups A and B. No permanent IAVN requiring pacemaker implantation was provoked in either group., Conclusion: RACP was useful to avoid sustained and serious IAVN during cryoablation of AVNRT., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Ultrastructural findings immediately after pulsed field ablation (PFA) of the myocardium have not been described., Objectives: The purpose of this study was to elucidate ultrastructural characteristics and differences between microsecond PFA at the 1- and 4-hour timepoints after pulse delivery and to compare them to irrigated radiofrequency ablation (RFA) lesions., Methods: Healthy swine underwent endocardial PFA or RFA followed by necropsy. Discrete microsecond PFA and irrigated RFA lesions were created in the ventricles with a lattice tip ablation catheter. Lesions were delivered in a manner so as to allow sampling to occur 1 and 4 hours after ablation. All lesions were located at necropsy, and samples were carefully obtained from within the lesion core, lesion periphery, and adjacent healthy myocardium. Transmission electron microscopic assessment was performed after fixation using paraformaldehyde and glutaraldehyde., Results: One hour after microsecond PFA delivery, myocytes were noted to be significantly and uniformly disrupted. Clustered, misaligned, swollen mitochondria coupled with degenerating nuclei and condensed chromatin were visualized. These findings progressed over the subsequent few hours with worsening edema. Similar changes were seen with RFA but reduced in severity. However, there was prominent extravasation of red blood cells with occlusion of capillaries that was not seen in PFA. At the lesion periphery, an abrupt change in the degree of myocyte damage was observed with PFA but not RFA., Conclusion: Transmission electron microscopy demonstrates evidence of widespread destruction of myocytes as early as an hour after PFA and corroborates known histologic features such as sparing of vessels and sharp lesion margins., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Periodontal disease (PD) is associated with an increased risk of cardiovascular disease (CVD). Pericardial adipose tissue (PAT) is known as a marker of progressive CVD. This study sought to assess the association between PD and PAT in patients with CVD., Methods: We retrospectively investigated 135 patients admitted for CVD who underwent computed tomography coronary angiography (CTCA) and periodontal examinations. Periodontal assessment using the community periodontal index (CPI) was based on the probing pocket depth around teeth. Patients with CPI ≥3 were categorized as having PD. PAT volume was measured with a quantitative semi-automated procedure using CTCA images. Patients were divided into tertiles according to PAT volume. Baseline characteristics and PD findings were compared among the tertiles., Results: Eighty-six patients were diagnosed with PD (63.7 %). Mean PAT volume was 181.4 ml, and patients were categorized as small-PAT (PAT <148.9 ml), intermediate-PAT (148.9 ml ≤ PAT ≤204.6 ml), and large-PAT (PAT >204.6 ml). The prevalence of PD was significantly higher in large-PAT (38/46, 82.6 %) than in small-PAT (18/45, 40.0 %) and intermediate-PAT (30/44, 68.2 %) patients. Multivariate logistic regression analysis showed that body weight, history of hypertension, and the presence of PD were independent predictors for large-PAT (odds ratio [OR]: 1.12, P  < 0.001, OR: 3.97, P  = 0.017, and OR: 4.18, P  = 0.0078, respectively)., Conclusion: The presence and severity of PD were significantly correlated with PAT volume, which has been associated with progressive CVD. Further prospective studies are warranted to assess the impact of PD on the onset and outcomes of CVD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: As cardiac implantable electronic devices, such as pacemakers, cardioverter defibrillators, and cardiac resynchronization therapies, have become more popular, device extraction has become more frequent. At our institution, individual treatment strategies are discussed at a heart team meeting. Transvenous lead extraction (TVLE) is a first-line treatment; however, surgical lead extraction (SLE) is sometimes selected as a primary choice to provide optimal treatment and maintain the medical safety policy. This study aimed to investigate the validity of this heart team decision-making., Methods: From 2013 to 2021, 384 consecutive patients underwent lead extraction at our institution., Results: SLE was proposed as the primary intervention for 21 patients who had high risk of bleeding, difficult TVLE conditions, large vegetations, and other concomitant cardiac diseases. Of the 363 TVLE patients, 10 patients required surgical intervention; 5 had TVLE difficulty followed by SLE and 5 had excessive bleeding. SLE was performed in 26 patients, 19 of whom required valve surgery, and 8 required plication of the great veins. In 4 of the 17 hybrid procedures with SLE and TVLE, excessive bleeding occurred due to laceration of the superior vena cava and innominate vein. Operative mortality was not observed in SLE patients but was observed in 1 of the 4 TVLE patients who required emergent open-chest hemostasis., Conclusions: The heart team discussion was essential to provide optimal treatment and maintain medical safety policies for each patient. SLE should be selected for patients with high risk of TVLE or other cardiac complications such as tricuspid valve incompetence., (Copyright © 2022. Published by Elsevier Ltd.)

Dopamine D1 receptor (D1R), coded by the Drd1 gene, is induced in cardiomyocytes of failing hearts, triggering heart failure-associated ventricular arrhythmia, and therefore could be a potential therapeutic target for chronic heart failure. The regulation of D1R expression, however, is not fully understood. Here, we explored the molecular mechanism by which cardiomyocyte D1R is induced in failing hearts. We performed motif analysis for the promoter region of the Drd1 gene using the transcription factor affinity prediction (TRAP) method and identified nuclear factor-kappa B (NF-κB) as a candidate transcriptional factor regulating the expression of the Drd1 gene. We next employed murine models of heart failure from chronic pressure overload by transverse aortic constriction (TAC), and assessed myocardial Drd1 expression levels and NF-κB activity, as well as endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of heart failure. Drd1 induction in TAC hearts was dependent on the severity of heart failure, and was associated with NF-κB activation and ER stress, as assessed by p65 phosphorylation and the expression of ER stress-related genes, respectively. We further tested if Drd1 was induced by ER stress via NF-κB activation in cultured neonatal rat ventricular myocytes. Tunicamycin activated NF-κB pathway in an ER stress-dependent manner and increased Drd1 expression. Importantly, inhibition of NF-κB pathway by pretreatment with Bay11-7082 completely suppressed the tunicamycin-induced upregulation of Drd1, suggesting that NF-κB activation is essential to this regulation. Our study demonstrates the pivotal role for the ER stress-induced NF-κB activation in the induction of D1R in cardiomyocytes. Intervention of this pathway might be a potential new therapeutic strategy for heart failure-associated ventricular arrhythmia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Although differential pacing conventionally has been used to confirm the achievement of block across linear lesion sets, high-resolution mapping demonstrates that pseudo-block is observed in 20%-30% of cases., Objectives: The purpose of this study was to examine the reliability and versatility of a method using "activation vectors" based on omnipolar technology to confirm the block line., Methods: Linear ablation was performed during pacing, with the HD Grid catheter (Abbott) placed beside the linear lesion opposite the pacing site. The endpoint of complete linear lesion was complete inversion of the activation vectors to the opposite direction. When inversion of the activation vectors was not observed after 10 minutes of radiofrequency (RF) application, high-resolution mapping was performed to assess whether complete block was achieved., Results: In 33 patients, 24 cavotricuspid isthmus lines, 11 mitral isthmus (MI) lines, 16 posterior lines, and 2 intercaval lines were performed using this method. Of the total of 53 lines, 10 (18.9%) required intermediate evaluation of the block line with high-resolution mapping because of the absence of inversion of activation vectors despite 10 minutes of RF application, resulting in incomplete block with endocardial gaps or epicardial conductions. Additional RF applications finally achieved inversion in direction of activation vectors in the 10 lines. In total, the present method can diagnose achievement of complete block line with 100% accuracy, whereas conventional differential pacing misdiagnosed incomplete block with epicardial conduction in posterior lines in 3 cases and in MI lines in 2 cases., Conclusion: Confirmation of complete linear lesions using "activation vectors" based on omnipolar technology is a reliable and versatile method., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The prognosis of patients with chronic limb-threatening ischemia (CLTI) is unacceptably poor, and risk factors are unknown. Serum remnant lipoprotein has been associated with cardiovascular events. The aim of our study was to test the hypothesis that remnant lipoprotein is associated with the prognosis of patients with CLTI., Methods: This retrospective study included 67 patients with CLTI who had received endovascular therapy (EVT) for de novo below-the-knee lesions. Patients were divided into 2 groups using fasting preoperative value of remnant-like particle cholesterol (RLP-C) with a cutoff value of 5.1 mg/dL into LOW RLP-C (n = 46) and HIGH RLP-C (n = 21). We assessed the differences between the 2 groups in the prevalence of major adverse limb events (MALE), composed of target lesion revascularization and major amputation., Results: At a median follow-up period of 12 months, MALE had occurred in 11 LOW RLP-C patients (23.9%) and 11 HIGH RLP-C patients (52.4%; P = 0.03). Kaplan-Meier analysis showed the prevalence of MALE was significantly higher in HIGH RLP-C than LOW RLP-C (log-rank χ 2  = 5.2, P = 0.02). Multivariate analysis found HIGH RLP-C to be an independent predictor for MALE (hazard ratio, 2.6; 95% confidence interval, 1.1-6.1; P = 0.02) along with history of coronary artery disease., Conclusions: Preoperative remnant lipoprotein was associated with the prognosis of patients with CLTI who had received EVT for de novo below-the-knee lesions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The vein of Marshall (VOM), which is surrounded by the Marshall bundle (MB), behaves as an epicardial connection bypassing the mitral isthmus. The influence of radiofrequency ablation and VOM ethanol infusion (VOM-EI) on epicardial MB conduction remains unclear., Objective: The purpose of this study was to evaluate MB conduction status during mitral isthmus ablation., Methods: Of 57 consecutive patients undergoing mitral isthmus ablation, 50 with electrode catheter cannulation into the VOM were analyzed. MB conduction was investigated by evaluating electrograms inside the VOM. Endocardial ablation was initially performed, followed by ablation inside the coronary sinus (CS), if required. Selective VOM-EI was performed if the MB potentials still exhibited early activation after radiofrequency ablation, suggesting the presence of MB connection bridging the mitral isthmus., Results: VOM electrograms composed of near-field MB and far-field left atrial potentials were recorded in all patients. Solely with endocardial ablation, 33 patients (66%) achieved entire mitral isthmus block, and 43 patients (86%) achieved an epicardial MB conduction block. MB potentials exhibited early activation in the remaining 7 (14%), even after requiring CS ablation. VOM-EI then was performed. Elimination of MB potentials was verified by electrode catheter reinsertion after VOM-EI. Mitral isthmus conduction was successfully blocked during VOM-EI in 4 patients and during additional radiofrequency ablation in the remaining 3. All patients finally achieved entire mitral isthmus block., Conclusion: MB is effectively ablated by radiofrequency ablation. Continuous evaluation of MB conduction can reveal epicardial conduction and ablation effect. A residual MB epicardial connection is relatively rare but can be ablated by VOM-EI., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Recent studies have reported that the lipid-rich plaque (LRP) detected by near-infrared spectroscopy (NIRS) and the pericoronary adipose tissue attenuation (PCATA) evaluated by coronary computed tomography angiography (CCTA) are associated with worse outcomes. We sought to investigate the relationship between NIRS-defined LRP and PCATA or the incremental ability of PCATA for the prediction of the presence of NIRS-defined LRP when added to the CCTA-derived morphometric findings., Methods: A total of 101 de novo lesions of 101 patients with chronic coronary syndromes (CCS), who underwent pre-procedural CCTA and NIRS during percutaneous coronary intervention (PCI), were retrospectively studied. PCATA was assessed by the crude analysis of the mean CT attenuation value of the culprit vessel. NIRS-defined LRP was defined as a maximum lipid core burden index in 4 mm ≥ 400. Univariate and multivariate logistic regression analyses were performed to determine the predictors of NIRS-defined LRP., Results: NIRS-defined LRP was observed in 37 patients and median PCATA was -72.71. A significant relationship was observed between LCBI and PCATA (r = 0.24, p = 0.001). PCATA (OR: 4.99; 95% CI: 1.48-16.82; p = 0.010) and CCTA-derived positive remodeling (OR: 12.53; 95% CI: 3.56-44.07; p < 0.001) were independent predictors of NIRS-defined LRP. Net reclassification and integrated discrimination improvement indices were both significantly improved when PCATA was added to the reference model including clinical characteristics and CCTA-derived morphometric findings., Conclusions: Comprehensive assessment of CCTA including PCATA may provide reliable information to identify the presence of NIRS-defined LRP potentially leading to future adverse events after PCI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The development of artificial intelligence (AI) began in the mid-20th century but has been rapidly accelerating in the past decade. Reflecting the development of digital health over the past few years, this trend is also seen in medicine. The field of cardiovascular medicine uses a wide variety and a large amount of biosignals, so there are many situations where AI can contribute. The development of AI is in progress for all aspects of the healthcare system, including the prevention, screening, and treatment of diseases and the prediction of the prognosis. AI is expected to be used to provide specialist-level medical care, even in a situation where medical resources are scarce. However, like other medical devices, the concept and mechanism of AI must be fully understood when used; otherwise, it may be used inappropriately, resulting in detriment to the patient. Therefore, it is important to understand what we need to know as a cardiologist handling AI. This review introduces the basics and principles of AI, then shows how far the current development of AI has come, and finally gives a brief introduction of how to start the AI development for those who want to develop their own AI., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest associated with this review., (Copyright © 2021. Published by Elsevier Ltd.)

Pyruvate dehydrogenase kinase 1 (PDK1) is a Ser/Thr kinase that inactivates mitochondrial pyruvate dehydrogenase (PDH), leading to switch of glucose metabolism from mitochondrial oxidation to aerobic glycolysis. We previously reported that PDK1 inhibition is a potent therapeutic strategy in multiple myeloma (MM). However, availability of PDK1 inhibitors, which are effective at low concentrations, are limited at present, making PDK1 inhibition difficult to apply in the clinic. In the present study, we examined the efficacy and mechanism of action of JX06, a novel PDK1 inhibitor, against MM cells. We confirmed that PDK1 is highly expressed in normal plasma cells and MM cells using publicly available gene expression datasets. JX06 suppressed cell growth and induced apoptosis against MM cells from approximately 0.5 μM JX06 treatment reduced PDH phosphorylation, suggesting that JX06 is indeed inhibiting PDK1. Intracellular metabolite analysis revealed that JX06 treatment reduced metabolites associated with glucose metabolism of MM cells. Additionally, JX06 in combination with a well-known proteasome inhibitor, bortezomib, significantly increased MM cell death, which raises the possibility of combination use of JX06 with proteasome inhibitors in the clinic. These findings demonstrate that PDK1 can be potentially targeted by JX06 in MM through glycolysis inhibition, leading to a novel therapeutic strategy in MM., Competing Interests: Declaration of competing interest Yawara Kawano reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. Yawara Kawano reports a relationship with Takeda Pharmaceutical Co Ltd that includes: speaking and lecture fees. Yawara Kawano reports a relationship with Sanofi that includes: speaking and lecture fees. Yawara Kawano reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Yawara Kawano reports a relationship with Ono Pharmaceutical Co Ltd that includes: speaking and lecture fees., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C-type lectin-like receptor 2 on platelets resulting in platelet activation. PDPN is expressed on lymphatic endothelial cells, perivascular fibroblasts/pericytes, cancer cells, cancer-associated fibroblasts, and tumor stromal cells. PDPN's expression on malignant epithelial cells plays a role in metastasis. Furthermore, the expression of PDPN in brain tumors (high-grade gliomas) was found to correlate with an increased risk of venous thrombosis., Objective: We examined the expression of PDPN and its role in tumor progression and venous thrombosis in ovarian cancer., Methods: We used mouse models of ovarian cancer and venous thrombosis., Results: Ovarian cancer cells express PDPN and release PDPN-rich extracellular vesicles (EVs), and cisplatin and topotecan (chemotherapies commonly used in ovarian cancer) increase the expression of podoplanin in cancer cells. The expression of PDPN in ovarian cancer cells promotes tumor growth in a murine model of ovarian cancer and that knockdown of PDPN gene expression results in smaller primary tumors. Both PDPN-expressing ovarian cancer cells and their EVs cause platelet aggregation. In a mouse model of venous thrombosis, PDPN-expressing EVs released from HeyA8 ovarian cancer cells produce more frequent thrombosis than PDPN-negative EVs derived from PDPN-knockdown HeyA8 cells. Blood clots induced by PDPN-positive EVs contain more platelets than those in blood clots induced by PDPN-negative EVs., Conclusions: In summary, our findings demonstrate that the expression of PDPN by ovarian cancer cells promotes tumor growth and venous thrombosis in mice., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Clinical significance of neoatherosclerosis (NA) observed at very late phase remains undetermined. We sought to investigate the association between NA observed by optical coherence tomography (OCT) 3-7 years after stenting and subsequent clinical outcomes., Methods: We investigated previously implanted stents without stent failure in the institutional OCT database at Tsuchiura Kyodo General Hospital. Qualitative and quantitative OCT analyses were performed. In patient-based analysis, major adverse cardiac events (MACE) included all-cause death, non-fatal myocardial infarction, and clinically driven revascularization. MACE-free survival rate was compared between patients with any stent showing NA (NA group) and those without NA (non-NA group). In stent-based analysis, the stent failure including target-lesion revascularization and stent thrombosis after the belated OCT examination were assessed., Results: A total of 187 patients with 308 stents undergoing belated OCT examination 3-7 years after implantation were investigated. Median duration from implantation to the belated OCT was 4.8 (3.8-5.8) years and NA was identified in 48 stents (15.6%) in 36 patients (19.3%). In patient-based analysis, during the median of 2.9 (2.1-3.6) years after belated OCT, MACE occurred in 9 patients (25.0%) with at least one stent showing NA (NA group) and 9 patients (6.0%) without NA (non-NA group) (p=0.002). Cox regression analysis revealed that NA was an independent predictor of MACE [hazard ratio (HR) 4.14 (1.58- 10.8), p=0.004]. In stent-based analysis, 7 stent failures were documented (stents with NA 10.0% vs. stents without NA 0.8%, p<0.01). NA was a significant predictor of stent failure [HR 9.17 (1.67- 50.3), p=0.011] at OCT examinations., Conclusions: NA observed by OCT 3-7 years after implantation was associated with subsequent worse clinical outcomes in both patient-based and stent-based analysis., Competing Interests: Disclosures None., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Centrifugal activation is not always the origin of a focal atrial tachycardia (AT) ("true-focal"), but passive activation from the other structures ("pseudo-focal")., Objective: We aimed to establish a method to differentiate true-focal from pseudo-focal., Methods: In 49 centrifugal activations in 35 patients with AT, 12-lead electrocardiogram, activation map, atrial global activation histogram (GAH), and local electrograms were analyzed. GAH demonstrates the relation between the activation area and timing through the cycle length, displayed with a normalized value, ranging from 0 (smallest activation area) to 1.0 (largest activation area)., Results: Of 30 centrifugal activations observed in the septal region, 6/30 (20.0%) were true-focal. The remaining 24/60 (80.0%) were pseudo-focal, of which 23 (95.8%) were from the opposite chamber. P-wave/flutter-wave duration < 200 ms discriminated true-focal from pseudo-focal (sensitivity 100%; specificity 54.5%; positive predictive value 33.3%; negative predictive value 100%). Multiple breakthrough ruled out the possibility of a true-focal AT. Other differentiating factors were an activation area within the initial 20 ms of <5 mm 2 and a typical QS pattern electrogram at the origin. Of 19 centrifugal activations observed outside the septal regions, 7 were true-focal and 12 were pseudo-focal exited from an epicardial structure: 10 of 12 (83.3%) were located around the left atrial appendage and ridge. Flutter wave, GAH score ≤ 0.05, and GAH score < 0.1 for >110 ms of cycle length differentiated true-focal from pseudo-focal with a sensitivity/negative predictive value of 100%. GAH score < 0.1 for >40% of the cycle length simply discriminated true-focal from pseudo-focal with 100% accuracy., Conclusion: Centrifugal activation is not necessarily due to a focal AT but passive activation. The activation map with GAH in addition to the 12-lead electrocardiogram and local electrograms enables an accurate differentiation., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Pericoronary adipose tissue attenuation expressed by fat attenuation index (FAI) on coronary CT angiography (CCTA) reflects pericoronary inflammation and is associated with cardiac mortality., Objective: The aim of this study was to define the sub-phenotypes of coronary CCTA-defined plaque and whole vessel quantification by unsupervised machine learning (ML) and its prognostic impact when combined with pericoronary inflammation., Methods: A total of 220 left anterior descending arteries (LAD) with intermediate stenosis who underwent fractional flow reserve (FFR) measurement and CCTA were studied. After removal of outcome and FAI data, the phenotype heterogeneity of CCTA-defined plaque and whole vessel quantification was investigated by unsupervised hierarchical clustering analysis based on Ward's method. Detailed features of CCTA findings were assessed according to the clusters (CS1 and CS2). Major adverse cardiac events (MACE)-free survivals were assessed according to the stratifications by FAI and the clusters., Results: Compared with CS2 (n = 119), CS1 (n = 101) were characterized by greater vessel size, increased plaque volume, and high-risk plaque features. FAI was significantly higher in CS1. ROC analyses revealed that best cut-off value of FAI to predict MACE was -73.1. Kaplan-Meier analysis revealed that lesions with FAI ≥ -73.1 had a significantly higher risk of MACE. Multivariate Cox proportional hazards regression analysis revealed that age, FAI ≥ -73.1, and the clusters were independent predictors of MACE., Conclusion: Unsupervised hierarchical clustering analysis revealed two distinct CCTA-defined subgroups and discriminated by high-risk plaque features and increased FAI. The risk of MACE differs significantly according to the increased FAI and ML-defined clusters., Competing Interests: Declaration of Competing Interest Dr. Bon-Kwon Koo received an Institutional Research Grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. Dr. Joo Myung Lee received a Research Grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. All other authors declare that there is no conflict of interest relevant to the submitted work., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We evaluated the 1-year success rate of maintaining sinus rhythm after catheter ablation (CA) for atrial fibrillation (AF) in patients with or without congestive heart failure (CHF)., Methods: In this single-centre retrospective matched-pair cohort study of 3,018 AF patients who underwent initial CA between January 2012 and June 2018, 227 pairs with (CHF group) or without CHF (control group) were matched using propensity scores. In the CHF group, 108 patients were assigned to the arrhythmia-induced cardiomyopathy (AIC) group whose left ventricular systolic dysfunction was explained only by lasting AF or atrial tachycardia; the remaining 119 had organic heart diseases (non-AIC group). We evaluated the 1-year AF-free survival and changes in clinical findings before and after CA., Results: The CHF and control groups showed similar AF-free survival; however, AIC patients had significantly better survival than non-AIC patients. AF recurrence was significantly related to CHF re-hospitalisation, which was significantly more frequent in the non-AIC group than in the AIC group. The clinical outcomes of left atrial dilation, brain natriuretic peptide level, and left ventricular ejection function improved significantly before and after CA in both groups. The degree of improvement was significantly better in the AIC group than in the non-AIC group., Conclusions: The 1-year success rate was not significantly different between the CHF and control groups. The 1-year success rate in the AIC group was similar to that in the AIC-control group and was better than that in the non-AIC group. CHF clinical outcomes were improved significantly., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: The nutritional risk of patients who undergo atrial fibrillation (AF) ablation varies. Its impact on the recurrence after ablation is unclear. We sought to evaluate the relationship between the nutritional risk and arrhythmia recurrence in patients who undergo AF ablation., Methods and Results: We enrolled 538 patients (median 67 years, 69.9% male) who underwent their first AF ablation. Their nutritional risk was evaluated using the pre-procedural geriatric nutritional risk index (GNRI), and the patients were classified into two groups: No-nutritional risk (GNRI ≧ 98) and Nutritional risk (GNRI < 98). The primary endpoint was a recurrence of an arrhythmia, and its relationship to the nutritional risk was evaluated. We used propensity-score matching to adjust for differences between patients with a GNRI-based nutritional risk and those without a nutritional risk. A nutritional risk was found in 10.6% of the patients, whereas the remaining 89.4% had no-nutritional risk. During a mean follow-up of 422 days, 91 patients experienced arrhythmia recurrences. The patients with a nutritional risk had a significantly higher arrhythmia recurrence rate both in the entire study cohort (Log-rank p = 0.001) and propensity-matched cohort (Log-rank p = 0.006). In a Cox proportional hazard analysis, the nutritional risk independently predicted arrhythmia recurrences in the entire study cohort (hazard ratio [HR]: 3.91, 95% confidence interval [CI]: 1.84-8.35, p < 0.001) and propensity-matched cohort (HR: 6.49, 95% CI: 1.42-29.8, p = 0.016)., Conclusion: A pre-procedural malnutrition risk was significantly associated with increased arrhythmia recurrences in patients who underwent AF ablation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The present study investigated the relationships between physiological indices and increased coronary flow during percutaneous coronary intervention (PCI) using a novel index of "anticipated maximum flow" [AMF; theoretical coronary flow of fractional flow reserve (FFR) = 1]. FFR-guided PCI aims to increase coronary flow, whereas recent studies have reported that PCI does not necessarily increase coronary flow despite improvement in FFR., Methods: This retrospective analysis was performed in 71 functionally significant lesions treated with elective PCI. AMF obtained by hyperemic average peak coronary flow velocity (h-APV) divided by FFR would not change after PCI given the constant microvascular resistance, which is the assumption of FFR as a surrogate of coronary flow. We evaluated the relationship between AMF and coronary flow during PCI., Results: Post-PCI AMF was significantly different from pre-PCI AMF (p = 0.022), which impacted discordance between FFR improvement and change in coronary flow. Coronary flow increase >50% was associated with smaller minimum lumen diameter (p = 0.010), greater diameter stenosis (p = 0.003), lower pre-PCI FFR (p < 0.001), lower pre-PCI coronary flow reserve (p = 0.001), higher pre-PCI hyperemic stenosis resistance (p < 0.001), lower pre-PCI h-APV (p = 0.001), and lower pre-PCI AMF (p = 0.031). Pre-PCI AMF provided significant incremental predictive capability for coronary flow increase >50% when added to the clinical model including pre-PCI FFR., Conclusion: Pre-PCI AMF provided incremental ability to predict increased coronary flow after PCI and impacted the discordance between FFR improvement and increased coronary flow., Competing Interests: Declarations of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Brain natriuretic peptide (BNP) predicts the prognosis in patients with atrial fibrillation (AF) and heart failure (HF); however, the level of BNP can change immediately after restoration of sinus rhythm. We aimed to investigate the clinical impact of serial change in BNP level before and after catheter ablation for AF, on the prognosis., Methods: In this retrospective single center study, 162 consecutive patients (67±9 years, 66.7% male) with AF and concomitant HF who underwent catheter ablation were examined. We analyzed the cardiac rhythm and % change in BNP pre- and post-ablation., Results: BNP increased by 32.7% (-4.5% to 51.3%) in patients with sinus rhythm at baseline (sinus rhythm group: N=50) and decreased by 47.6% (20.9 to 61.6%) in patients with AF rhythm at baseline. Patients with AF rhythm at baseline were categorized into two groups according to the median value of reduction in % BNP; patients with good % BNP reduction (good BNP-R group; N=56), and with poor % BNP reduction (poor BNP-R group; N=56). Although the rate of recurrence of AF after ablation was comparable between the good and poor BNP-R groups, poor BNP-R was an independent predictor of subsequent composite events including HF hospitalization, ischemic stroke, and all cause of death after ablation, even after adjusting for other confounders (hazard ratio: 6.85, 95% confidence interval: 2.16 to 21.7, p-value=0.001). In the longitudinal analysis of echocardiographic parameters, shortening of the left ventricular end-diastolic diameter with preserved ejection fraction was evident except in the poor BNP-R group., Conclusion: In patients with AF and HF, poor % BNP reduction was an independent predictor of adverse outcome, although the rate of recurrence of AF was comparable. Serial BNP measurement might help in better identification of high-risk patients in whom sinus rhythm is restored with catheter ablation., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: The objective of this study was to investigate the clinical characteristics of hemodialysis patients with peripheral artery disease (PAD) and the outcomes after endovascular therapy (EVT) in such patients stratified by the primary kidney disease., Methods: This retrospective observational study evaluated 142 consecutive hemodialysis patients with symptomatic PAD who underwent EVT (men: n = 103, age: 74 ± 8 years). Patients were divided into 3 groups in accordance with the reason for hemodialysis: hypertensive nephrosclerosis (HTN [n = 26]), diabetic nephropathy (DN [n = 85]), and chronic glomerulosclerosis (CGN [n = 31]). The primary outcome was major adverse event(s) (MAEs), including target lesion revascularization, major amputation, and all-cause death. Clinical characteristics and outcomes were compared among the 3 groups., Results: Patients with HTN were older (81 ± 6 years vs. 72 ± 8 years vs. 74 ± 8 years; P < 0.001) and had a shorter hemodialysis vintage (2.4 years vs. 6.8 years vs. 11.2 years; P < 0.001) than those with DN and CGN. Critical limb ischemia (CLI) affected 15 (58%) patients in the HTN group, 52 (61%) in the DN group, and 10 (32%) in the CGN group. Target lesion length was longer in patients with HTN than in those in the other groups (155 ± 101 mm vs. 108 ± 77 mm [DN] vs. 98 ± 76 mm [CGN]; P = 0.020). During a median follow-up period of 372 days (interquartile range, 198-730 days), Kaplan-Meier curve analysis revealed that HTN was associated with an increased risk for MAEs (χ 2 11.6; P = 0.003). Furthermore, multivariate Cox regression analysis revealed that CLI, HTN, and B-type natriuretic peptide levels were independent predictors of MAE (hazard ratio 3.91, 2.88, and 1.00; P < 0.001, P < 0.001, and P = 0.001, respectively)., Conclusions: Among hemodialysis patients with PAD, HTN was associated with an increased risk for MAEs after EVT., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ablation using radiofrequency energy has to be carefully performed when the arrhythmia substrate is located in close proximity to the atrioventricular (AV) node due to the risk of inadvertent permanent AV block. The aim of this study was to evaluate the efficacy and safety of catheter-based cryo-therapy for septal accessory pathways (APs)., Methods: A total of eleven patients (median = 56.3 years, range 13-74 years) with septal APs underwent cryoablation. Ice-mapping was performed during sinus rhythm and an AV reciprocating tachycardia utilizing the APs as a requisite limb with cooling of the catheter tip temperature to a maximum of -30℃ for less than 45 s. Cryo-ablation was performed for 4 min at a temperature of -80℃ only if ice-mapping abolished the pre-excitation or retrograde conduction over the AP without injury to the AV nodal conduction., Results: Cryo-ablation was acutely successful in all eleven patients. No permanent cryo-related complications or adverse outcomes were reported. During the follow-up (range 14-26 months), no patients experienced any arrhythmia recurrences., Conclusion: Ice-mapping was a feasible and reliable method to determine the exact location of the APs owing to the possibility of validating the ablation site. Cryo-ablation of APs located near the AV junction is a safe and efficacious technique with a high success rate over the long term., Irb Information: Ethical Committee of Japan Red Cross Yokohama City Bay Hospital #2018-19., (Copyright © 2020. Published by Elsevier Ltd.)

Background and Aim: Eicosapentaenoic acid (EPA) has been reported to improve clinical outcome of high-risk atherosclerotic patients. We investigated whether endogenous EPA values predict prognosis of peripheral artery disease (PAD) patients., Methods and Results: This retrospective study included 166 consecutive patients who had received endovascular therapy (EVT) for PAD caused by aortoiliac artery lesions. Patients were divided into 2 groups using median preoperative EPA value (57 μg/ml): LOW EPA (n = 83) and HIGH EPA (n = 83). We compared differences between the 2 groups in prevalence of major adverse limb events (MALE) which included target lesion revascularization (TLR), non-TLR, and major amputation, and major adverse events (MAE) which included MALE and all cause death. At a median follow-up period of 20 months, MALE had occurred in 24 LOW EPA patients (28.9%) and in 12 HIGH EPA patients (14.5%) (p = 0.04), and MAE had occurred in 41 LOW EPA patients (49.4%) and in 21 HIGH EPA patients (25.3%) (p < 0.01). Kaplan-Meier analysis showed prevalence of MALE and MAE was significantly higher in LOW EPA than in HIGH EPA (long-rank test χ 2  = 8.5, p < 0.01, log-rank test χ 2  = 13.2, p < 0.01, respectively). Multivariate Cox regression revealed preoperative EPA value < 57 μg/ml was an independent predictor for MALE (hazard ratio [HR]: 2.70; 95% CI: 1.35 to 5.4; p < 0.01) and MAE (HR: 2.86; 95% CI: 1.67 to 4.91; p < 0.01)., Conclusions: Endogenous EPA value seems to be associated with risk of MALE and MAE after EVT in patients with PAD caused by aortoiliac artery lesions., Competing Interests: Declaration of competing interest The all authors have no conflicts of interest to declare., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: There remains a residual risk for acute myocardial infarction (AMI) even with low low-density lipoprotein cholesterol (LDL-C) levels. This study aimed to characterize the culprit lesion morphology of AMI by optical coherence tomography (OCT) in patients with low LDL-C., Methods: Four-hundred and nine culprit lesions of 409 patients with their first presentation of AMI imaged by OCT were investigated. OCT analysis included the presence of plaque rupture and thin-capped fibroatheroma (TCFA). Fibrous cap thickness and lipid length were also measured. Intravascular ultrasound (IVUS) was performed in 368 (90.0%) patients. OCT and IVUS findings were compared between patients with LDL-C < 100 mg/dl (lower-LDL group) and those with LDL ≥ 100 mg/dl (higher-LDL group)., Results: Lower-LDL group included 93 (22.7%) patients. Plaque rupture (54.8% vs. 68.7%, p = 0.018) and TCFA (39.8% vs. 54.6%, p = 0.013) were less frequently observed in lower-LDL than in higher-LDL. Fibrous cap was thicker [73 (59-109) µm vs. 63 (57-83) µm, p = 0.028] and lipid length was smaller [5.4 (2.3-9.9) mm vs. 7.1 (4.1-10.5) mm, p = 0.012] in lower-LDL than in higher-LDL. There were no significant differences in IVUS parameters including plaque burden or remodeling index between the two groups., Conclusions: Patients with lower LDL-C showed more prevalent intact fibrous cap and less vulnerable features in the culprit lesions, which may suggest the need for exploring a specific strategy for the prevention of plaque erosion in low LDL-C subjects., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Catheter manipulation in the left-sided heart is known as a risk for cerebral embolisms (CEs). However, anticoagulation therapy is terminated before catheter ablation (CA) of atrial fibrillation (AF) concerning adverse bleeding events. Little is known whether uninterrupted direct oral anticoagulants (DOACs) during perioperative period of CA could render the ablation procedure safer and reduce the incidence of CEs compared to interrupted DOACs. The aim of this study was to investigate the safety and usefulness of uninterrupted dabigatran during the periprocedural period for CA of AF., Methods: We included 333 patients with paroxysmal AF undergoing cryoballoon CA (CBA). They were prospectively divided into 2 groups based on whether DOACs were interrupted on the day of the CA (Group A, n=228) or dabigatran was not interrupted throughout perioperative period (Group B, n=105) in a non-randomized fashion. When the Group B patients had taken other DOACs rather than dabigatran before assignment, we changed those DOACs to dabigatran. Brain magnetic resonance imaging (MRI) was undertaken on the following day of the CA. Serious bleeding event cases were excluded from the study., Results: The baseline characteristics including the CHADs2 score did not exhibit any significant differences between the groups. The brain MRI revealed an acute CEs in 82 patients, and was significantly higher in Group A than B (29% vs. 13%, respectively, p<0.01). There were no significant differences regarding the bleeding events (7% vs. 4%, respectively, p=0.62)., Conclusion: Uninterrupted dabigatran therapy during the CBA of paroxysmal AF could significantly reduce the incidence of CEs., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The left atrial myocardium (LAM) and coronary sinus (CS) musculature (CSM) generate atrial electrograms recorded inside the CS (AECSs). The vein of Marshall (VOM) courses the mitral isthmus (MI), and ethanol infusion into the VOM (EI-VOM) is useful to ablate it. However, its detailed effect on the MI, which contains the LAM, CSM, and those connections, is unknown., Objective: The purpose of this study was to investigate the impact of EI-VOM on the MI by assessing the AECS., Methods: Eighty-four consecutive patients with atrial fibrillation undergoing MI ablation with successful EI-VOM were included. After EI-VOM, radiofrequency (RF) catheter touchup ablation was performed at MI gap sites or inside the CS (RFCS), as needed, to achieve bidirectional conduction block. Ablation effects on AECSs were evaluated during the MI ablation procedure., Results: AECSs demonstrated double potentials consisting of low-amplitude LAM components and high-amplitude CSM components in 31 patients (37%). Of those patients, 21 had a distal-to-proximal activation sequence of the LAM along with a proximal-to-distal activation sequence of the CSM during left atrial appendage pacing, suggesting CSM isolation from the LAM due to electrical LAM-CSM disconnection. Only 2 of the 21 patients required RFCS. The remaining 10 patients with distal-to-proximal activation in both CSM and LAM, suggesting incomplete CSM isolation and persistent LAM-CSM conduction, required RFCS. Overall, combined EI-VOM with RF created bidirectional conduction block at the MI in 78 patients (93%)., Conclusion: EI-VOM can ablate the LAM and myocardial connections between the LAM and CSM. Careful assessment of AECSs can predict a requirement for RFCS., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Oral cancer and smoking are closely related, because the oral cavity, which is the route of ingestion of tobacco smoke, is in direct contact with the oral mucosa. Nicotine, one of the components of tobacco, can diffuse rapidly to the central nervous system and is responsible for tobacco addiction. Nicotine is present in high concentrations in the bloodstream of smokers; while the addictive effects of this alkaloid have extensively been studied, its effect on tumorigenesis is not clear yet. Therefore, in this study, we examined the effect of nicotine on cell proliferation and the signaling pathways it activates. The human oral squamous cell carcinoma cell line HSC-2 was used as a model system. We demonstrated the correlation between nicotine and epidermal growth factor receptor (EGFR) signaling. Nicotine treatment induced HSC-2 cell proliferation and migration and the phosphorylation of EGFR. Furthermore, nicotine treatment activated the EGFR downstream effectors phosphatidylinositol-3 kinase/AKT and p44/42 mitogen-activated protein kinases (ERK), which, in turn, promoted cell proliferation. Overall, our study suggests that nicotine promotes cell growth and migration through epidermal growth factor (EGF) signaling and plays an important role in oral cancer progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Adenosine triphosphate (ATP) can provoke acute reconnections after pulmonary vein isolation (PVI). This study aimed to investigate dormant conduction (DC) after ablation with second-generation cryoballoon (CB)., Methods: Two hundred sixteen patients (148 male; age 64±9 years) with atrial fibrillation (AF) were included. After a successful PVI with the CB, 20mg of ATP was administered. All patients were followed up for 425±56 days., Results: Seven hundred ninety-five out of 864 (92%) PVs were successfully isolated solely by the CB. DCs were revealed in 8 (3.7%) after ATP injections. AF recurrences occurred in 2 out of 8 patients, while no AF recurrences could be documented in 6 out of 8 patients with DCs after a blanking period of 3 months (25% vs. 75%). In contrast, 29 (13.9%) patients without DCs had AF recurrences, and there was no significant difference between those with and without DCs regarding the recurrence rate of AF (p=0.38). There were no reliable predictors of DCs after the PVI with the CB., Conclusion: The present study demonstrated a low rate of transient PV reconnection after adenosine infusion following successful PVI with the CB. There was no reliable predictor of DCs. Further studies will be needed in order to appreciate the prognostic value of adenosine testing after successful PVI with the CB., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aim: We aimed to study a single nucleotide polymorphism (SNP), rs2106261, in the transcription factor gene, ZFHX3, in atrial fibrillation (AF) and other related phenotypes by phenome scanning in a Japanese population., Method: We retrieved consecutive autopsy data (n=2433, mean age=80 years) from the Japanese SNP database for geriatric diseases (JG-SNP). Clinical data, including an AF diagnosis, were collected from medical charts. Genotyping was performed with the DNA chip method. We also analyzed 42 pathological and 26 clinical phenotypes, including cerebral infarctions (CIs) and lung thromboembolisms (LTs), diagnosed by macroscopic inspection during the autopsy., Result: Among the 2433 patients with available data, 18.6% had AF, 29.4% had CI, and 4.9% had LT phenotypes. The A allele of the rs2106261 SNP was significantly associated with AF, after adjusting for age, sex, diabetes, hypertension, and smoking (AA+AG/GG, OR=1.51, 95%CI: 1.16-1.97, p=0.002). In the entire cohort, CI was not associated with rs2106261 (p=0.14). However, among patients under 80 years old, rs2106261 was significantly associated with CI (AA+AG/GG, OR=1.57, 95%CI: 1.09-2.26, p=0.01). LT was also associated with rs2106261 (AA+AG/GG, OR=1.99, 95%CI: 1.31-3.01, p=0.001). Associations between rs2106261 and CI and LT remained positive after adjusting for the presence of AF, which indicated that this SNP variant might serve as an independent risk marker., Conclusion: We showed that the ZFHX3 polymorphism, rs2106261 (A allele), was a risk marker for AF and AF-related phenotypes. The roles of this variant in the development of AF and its related phenotypes warrant further investigation., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: Few data exist to evaluate the safety and efficacy of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) undergoing cryoballoon ablation (CB-A). This study is aimed to clarify the usefulness of DOACs in patients undergoing CB-A., Methods: The patients (average age; 65.8±11.9 years old, male 69%) were stratified into one of five subsets based on the type of anticoagulation (warfarin, apixaban, dabigatran, rivaroxaban, or edoxaban), and underwent CB-A. A brain MRI was performed in all patients the day after the CB-A for AF. A total of 257 (19 on warfarin, 30 on apixaban, 66 on dabigatran, 81 on rivaroxaban, and 61 on edoxaban) patients met the inclusion criteria., Results: The incidence of silent cerebral ischemic lesion was 1 (11.1%) patients on warfarin, 5 (33.3%) on apixaban, 8 (27.6%) on dabigatran, 10 (21.3%) on rivaroxaban, and 10 (29.4%) on edoxaban (p=0.17). Major ischemic events occurred in one patient (1.6%) on edoxaban and one (5.3%) on warfarin. Minor bleeding complications occurred in 1 patient (5.3%) on warfarin, 2 (6.7%) on apixaban, 1 (1.2%) on rivaroxaban, 5 (7.6%) on dabigatran, and 2 (3.3%) on edoxaban (p=0.24). Of note, major bleeding complications occurred in 2 patients (3.3%) on apixaban, 1 (1.2%) on rivaroxaban, 1 (1.5%) on dabigatran, 1 (1.6%) on edoxaban, and 2 (10.5%) on warfarin (p<0.05)., Conclusions: Warfarin use significantly increased the risk of serious bleeding, in contrast, CB-A did not place the patients at an increased risk of complications under a DOAC treatment. There were no significant differences regarding preventing embolic events among the DOAC drugs., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the optimal scan settings (scan mode and position of field of view [FOV]) for cone beam computed tomography to reduce root fracture-like artifacts that are often observed in teeth filled with gutta-percha cones (GPCs)., Study Design: Fracture-like artifacts that appeared on cone beam computed tomography images of 9 extracted human mandibular premolars filled with GPCs were analyzed using I-mode (FOV, 102 mm; voxel size, 0.2 mm) and D-mode (FOV, 51 mm; voxel size, 0.1 mm) settings., Results: The artificial lines were more obvious in I-mode than in D-mode. Increased distance between the center of the FOV and the GPCs produced stronger artificial lines in both I-mode and D-mode., Conclusion: To reduce fracture-like artifacts, it is critical to use a mode with small voxel size and to place the target tooth in the center of the FOV., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Diaphragmatic electrogram recording during cryoballoon ablation (CB-A) of atrial fibrillation is commonly used to predict phrenic nerve palsy (PNP)., Objective: The purpose of this study was to investigate a novel method for predicting PNP at an earlier stage to prevent sustained PNP., Methods: A total of 197 patients undergoing CB-A were enrolled. We attempted to detect PNP using fluoroscopic images of diaphragmatic contractions and by monitoring diaphragmatic compound motor action potentials (CMAPs) provoked by superior vena cava (SVC) and left subclavian vein (LCV) pacing during CB-A for bilateral pulmonary veins (PVs). Pacing of the SVC and LCV was performed at 2 outputs, 1 exceeding the pacing threshold by 10% (MIN) and the other at maximum output (MAX). The time from freezing to the initiation of PNP, values of the CMAP amplitude, and severity of PNP were compared for the 2 outputs., Results: There was a significant difference in the time from freezing to initiation of PNP between MIN and MAX pacing (25.7 ± 5.7 vs 81.3 ± 7.4 seconds, P<.01). CMAP amplitudes also differed significantly (0.71 ± 0.39 vs 1.13 ± 0.42, P<.0001). SVC/LCV pacing with MIN output was able to detect PNP significantly earlier than MAX (27 ± 8 vs 91 ± 12 seconds, P<.01), and the time to PNP recovery was significantly shorter for the MIN output (20.2 ± 8.88 hours vs 4.8 ± 1.6 months, P<.001)., Conclusion: Pacing the SVC and LCV with lower output detect PNP significantly earlier than maximal output pacing and leads to recovery from PNP on the order of hours postprocedure rather than months., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objective: To clarify the cause of artificial tooth-root fracture lines in cone beam computed tomography (CBCT) images caused by root canal filling materials and to enhance the diagnostic performance of CBCT., Study Design: We analyzed the CBCT images of 18 extracted human teeth (9 upper central incisors and 9 lower premolars) that were filled with a size 50 gutta-percha cone and inserted into tooth sockets in a human skull., Results: The CBCT images of the incisors displayed artificial lines in the oblique directions, notably the mesiobuccal, distolingual, distobuccal and mesiolingual directions, but only rarely in the cross-directions (buccal, lingual, mesial, and distal). In the premolars, the reverse was true, with lines mainly in the cross-directions, mesial and distal directions particularly. The lines were predominantly at the cervical slice., Conclusions: Artifacts resulting from root filling material appear along the long axis of the alveolar bones, and resemble root fractures., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Thymine DNA glycosylase (TDG) is a base excision repair enzyme that interacts with the small ubiquitin-related modifier (SUMO)-targeted ubiquitin E3 ligase RNF4 and functions in the active DNA demethylation pathway. Here we showed that both SUMOylated and non-modified forms of endogenous TDG fluctuated during the cell cycle and in response to drugs that perturbed cell cycle progression, including hydroxyurea and nocodazole. Additionally, we detected a SUMOylation-independent association between TDG and RNF4 in vitro as well as in vivo, and observed that both forms of TDG were efficiently degraded in RNF4-depleted cells when arrested at S phase. Our findings provide insights into the in vivo dynamics of TDG SUMOylation and further clarify the TDG-RNF4 interaction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

RNF4, a SUMO-targeted ubiquitin ligase (STUbL), localizes to the nucleus and functions in the DNA damage response during interphase of the cell cycle. RNF4 also exists in cells undergoing mitosis, where its regulation and function remain poorly understood. Here we showed that administration of etoposide, an anticancer DNA topoisomerase II poison, to mitotic human cervical cancer HeLa cells induced SUMO-2/3-dependent localization of RNF4 to chromosomes. The FK2 antibody signals, indicative of poly/multi-ubiquitin assembly, were detected on etoposide-exposed mitotic chromosomes, whereas the signals were negligible in cells depleted for RNF4 by RNA interference. This suggests that RNF4 functions as a STUbL in the etoposide-induced damage response during mitosis. Indeed, RNF4-depletion sensitized mitotic HeLa cells to etoposide and increased cells with micronuclei. These results indicate the importance of the RNF4-mediated STUbL pathway during mitosis for the maintenance of chromosome integrity and further implicate RNF4 as a target for topo II poison-based therapy for cancer patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this article was to test the theory that short miniscrews will decrease the possibility of damaging the root, but the failure rate will increase., Methods: One hundred eighty-six miniscrews (diameter, 1.3 × 5 mm, n = 63; 6 mm, n = 62; 7 mm, n = 61) were placed in 105 consecutive patients. Multislice computed tomography and cone-beam computed tomography scans were taken before and after miniscrew placement. Insertion torque was measured at miniscrew placement., Results: The success rate of the miniscrews in the maxilla (93.4%) was higher than that in the mandible (70.3%). A significantly lower success rate with 5-mm miniscrews was observed compared with 6-mm and 7-mm miniscrews in the mandible. Miniscrews placed in less than approximately 3.8 mm of bone and those within 1.4 mm of the root had significantly higher failure rates. Miniscrews placed with insertion torque greater than 10 Ncm had a tendency for a lower success rate., Conclusions: The optimum lengths of miniscrews of a diameter of 1.3 mm are 5 mm in the maxilla and 6 mm in the mandible. They should be placed at a distance from the root with insertion torque less than 10 Ncm for safe orthodontic anchorage without failure., (Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Background: Dabigatran has demonstrated promising results for the prevention of strokes in patients with non-valvular atrial fibrillation (NVAF). However, there have been episodes of major bleeding, especially in elderly patients or those with renal dysfunction. The purpose of this study was to retrospectively examine the relationship between the bleeding events and activated partial thromboplastin time (APTT) values under dabigatran usage in the everyday clinical practice. Moreover, we investigated which factors would contribute to the APTT values., Methods and Results: A total of 139 NVAF patients (112 men, 65 ± 11 years) were included. We evaluated the influence of the putative etiological variables and the bleeding score, HAS-BLED score, on APTT values: age greater than 70 years, renal function, gender, dose of dabigatran, and the concomitant prescription of a P-glycoprotein inhibitor. There were 50 patients with an age of ≥ 70 years (36.0%). A P-glycoprotein inhibitor was administered in 18 patients. During the observation period (median 120 days) there was 1 episode of asymptomatic cerebral infarction. There were no intrinsic major bleeding events, however, 11 patients had minor hemorrhagic events. The results of the APTT measurements exhibited a variety of values both among inter- and intra-individuals. On multivariable analysis, significant associations were found between the following risk factors and the APTT values: creatinine clearance, dose of dabigatran, and concomitant use of a P-glycoprotein inhibitor. The minor bleeding events did not correlate with the APTT values, nor HAS-BLED score., Conclusions: The APTT values became prolonged under dabigatran usage and exhibited a remarkable diversity. Although major bleeding did not occur unless APTT was prolonged excessively, minor bleeding arose irrespective of the APTT values even within the range of the APTT values not exceeding 80s., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)